In vivo photorelease of GABA in the mouse cortex

Electrical stimulation has been used for more than 100 years in neuroscientific and biomedical research as a powerful tool for controlled perturbations of neural activity. Despite quickly driving neuronal activity, this technique presents some important limitations, such as the impossibility to activate or deactivate specific neuronal populations within a single stimulation site. This problem can be avoided by pharmacological methods based on the administration of receptor ligands able to cause specific changes in neuronal activity. However, intracerebral injections of neuroactive molecules inherently confound the dynamics of drug diffusion with receptor activation. Caged compounds have been proposed to circumvent this problem, for spatially and temporally controlled release of molecules. Caged compounds consist of a protecting group and a ligand made inactive by the bond between the two parts. By breaking this bond with light of an appropriate wavelength, the ligand recovers its activity within milliseconds. To test these compounds in vivo, we recorded local field potentials (LFPs) from the cerebral cortex of anesthetized female mice (CF1, 60-70 days, 20-30 g) before and after infusion with caged γ-amino-butyric-acid (GABA). After 30 min, we irradiated the cortical surface with pulses of blue light in order to photorelease the caged GABA and measure its effect on global brain activity. Laser pulses significantly and consistently decreased LFP power in four different frequency bands with a precision of few milliseconds (P < 0.000001); however, the inhibitory effects lasted several minutes (P < 0.0043). The technical difficulties and limitations of neurotransmitter photorelease are presented, and perspectives for future in vivo applications of the method are discussed.

Diseño de la DL-4-hidroxi, 4-etil, 4-fenil butiramida (HEPB) y sus homólogos inferiores / Design of DL-4-hydroxy, 4-ethyl, 4-phenyl butyramide (DL-HEPB) and its inferior homologues

En 1962 sintetizamos una serie de nuevos fármacos originalmente planeados como inhibidores de la transaminasa del ácido-aminobutírico-ácido-cetoglutárico, mediante la sustitución de los átomos de hidrógeno del carbono gamma de la molécula cíclica del ácido gamma aminobutírico por los grupos etilo y fenilo, metilo y fenilo y difenilo. Los estudios de resonancia magnética y de difracción de rayos X revelaron que estos compuestos son fenilalcoholamidas. En una serie de estudios farmacológicos, electrofisiológicos y de comportamiento, así como estudios clínicos preliminares, la DL-4-hidroxi, 4-etil, 4-fenil butiramida (HEPB) demostró poseer una actividad anticonvulsionante poderosa. Por lo tanto, hemos sintetizado los homólogos propionamida y acetamida del HEPB con la meta de obtener anticonvulsionantes más potentes y menos tóxicos. La caracterización de estos compuestos se está llevando a cabo mediante los esfuerzos de un progama multidisciplinario de varios grupos de investigación en diferentes instituciones mexicanas